US3342681A - Antibiotic armentomycin and a process for producing the same - Google Patents

Antibiotic armentomycin and a process for producing the same Download PDF

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US3342681A
US3342681A US448611A US44861165A US3342681A US 3342681 A US3342681 A US 3342681A US 448611 A US448611 A US 448611A US 44861165 A US44861165 A US 44861165A US 3342681 A US3342681 A US 3342681A
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armentomycin
water
armentosus
antibiotic
growth
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Alexander D Argoudelis
Ross R Herr
Donald J Mason
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Pharmacia and Upjohn Co
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Upjohn Co
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Priority to GB13338/66A priority patent/GB1131079A/en
Priority to DE19661617902 priority patent/DE1617902A1/de
Priority to NL6604978A priority patent/NL6604978A/xx
Priority to FR57889A priority patent/FR1487346A/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
    • C10M1/00—Liquid compositions essentially based on mineral lubricating oils or fatty oils; Their use as lubricants
    • C10M1/08—Liquid compositions essentially based on mineral lubricating oils or fatty oils; Their use as lubricants with additives
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
    • C10M2215/00—Organic non-macromolecular compounds containing nitrogen as ingredients in lubricant Compositions
    • C10M2215/02—Amines, e.g. polyalkylene polyamines; Quaternary amines
    • C10M2215/04—Amines, e.g. polyalkylene polyamines; Quaternary amines having amino groups bound to acyclic or cycloaliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10M—LUBRICATING COMPOSITIONS; USE OF CHEMICAL SUBSTANCES EITHER ALONE OR AS LUBRICATING INGREDIENTS IN A LUBRICATING COMPOSITION
    • C10M2215/00—Organic non-macromolecular compounds containing nitrogen as ingredients in lubricant Compositions
    • C10M2215/24—Organic non-macromolecular compounds containing nitrogen as ingredients in lubricant Compositions having hydrocarbon substituents containing thirty or more carbon atoms, e.g. nitrogen derivatives of substituted succinic acid
    • C10M2215/26—Amines
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
    • C10N2040/00—Specified use or application for which the lubricating composition is intended
    • C10N2040/20—Metal working
    • C10N2040/22—Metal working with essential removal of material, e.g. cutting, grinding or drilling
    • C—CHEMISTRY; METALLURGY
    • C10—PETROLEUM, GAS OR COKE INDUSTRIES; TECHNICAL GASES CONTAINING CARBON MONOXIDE; FUELS; LUBRICANTS; PEAT
    • C10N—INDEXING SCHEME ASSOCIATED WITH SUBCLASS C10M RELATING TO LUBRICATING COMPOSITIONS
    • C10N2050/00—Form in which the lubricant is applied to the material being lubricated
    • C10N2050/015—Dispersions of solid lubricants
    • C10N2050/02—Dispersions of solid lubricants dissolved or suspended in a carrier which subsequently evaporates to leave a lubricant coating
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/886—Streptomyces

Definitions

  • This invention relates to a novel composition of matter and to a process for the production thereof. More particularly, this invention relates to a new compound, armentomycin (U-10,923), and to a process for the production thereof.
  • Armentomycin is a biosynthetic product produced by culturing an armentomycin-producing actinomycete in an aqueous nutrient medium. It is an amphoteric substance which has the property of adversely affecting the growth of certain organisms, particularly bacteria, for example, Pseudomonas aerzigz'nosa, Proteus vulgaris, Proteus mirabilis, Salmonella gallinarum, Proteus retlgeri, and Escherichia cOli, and can be used alone or in combination with other antibacterial agents to prevent the growth of, or reduce the number of, such organisms present in various environments.
  • bacteria for example, Pseudomonas aerzigz'nosa, Proteus vulgaris, Proteus mirabilis, Salmonella gallinarum, Proteus retlgeri, and Escherichia cOli, and can be used alone or in combination with other antibacterial agents to prevent the growth of, or
  • it can be used in paper mill systems to inhibit the growth of Aerobacier aerogenes which is known to produce slime in such systems. It is also useful as an oil preservative, for example, as a bacteriostatic agent for inhibiting the growth of Proteus vulgar-is which is known to cause spoilage in cutting oils. Also, it is useful in wash solutions for sanitation purposes, as in the washing of hands and the cleaning of equipment, floors, or furnishings of contaminated rooms or laboratories; it is also useful as an industrial preservative, for example, as a bacteriostatic rinse for laundered clothes and for impregnating paper and fabrics; and it is useful for suppressing the growth of sensitive organisms in plate assays and other biological media. It can also be used as a feed supplement to promote the growth of animals, for example, mammals, birds, fish, and reptiles.
  • the microorganism The actinomycete used according to this invention for the production of armentomycin has been designated as S. armentosus var. armentosus nov. sp.
  • One of its strain characteristics is the production of armentomycin.
  • a subculture of the living organism can be obtained from the permanent collection of the Northern Utilization and Research Division, Agricultural Research Service, U.S. Department of Agriculture, Peoria, 111., U.S.A. Its accession number in this repository is NRRL 3176.
  • ARMENTOSUS Medium Surface (Aerial Reverse Pigment Other Growth) P .I A ar White Melaninrlz. 02%;123; h /i l ate Agann Malate solubilized. Glucose Asparagine Agar None. Skim Milk Agar Casein solubilized around growth. Tyrosine Agar Tyrosine solubllrzed. Xanthine Agar Xanthine solubilized. Casein Starch Agar Starch solubilized. Tomato Paste Oatmeal None. Synthetic Nitrate Broth N reduction. Nutrient Nitrate Broth o. Litmus Milk Some peptomzation pH 7.1.
  • the new compound of the invention is produced when the elaborating organism is grown in an aqueous nutrient medium under submerged aerobic conditions. It is to be understood also that for the preparation of limited amounts surface cultures in bottles can be employed.
  • the organism is grown in a nutrient medium containing a carbon source, for example, an assimilable carbohydrate, and a nitrogen source, for example, an assimilable nitrogen compound or proteinaceous material.
  • a carbon source for example, an assimilable carbohydrate
  • a nitrogen source for example, an assimilable nitrogen compound or proteinaceous material.
  • Preferred carbon sources include glucose, brown sugar, sucrose, glycerol, starch, corn starch, galactose, dextrin, molasses, and the like.
  • Preferred nitrogen sources include com steep liquor," yeast, autolyzed brewers yeast with milk solids, soybean'meal, cottonseed meal, corn meal, milk solids, pancreatic digest of casein, distillers solubles, fish meal, animal peptone liquors, meat and bone scraps, and the like
  • Trace metals for example, zinc, magnesium, manganese, cobalt, iron, and the like need not be added to the fermentation since tap water and unpurified ingredients are used as media components.
  • Production of the compound of the invention can be effected at any temperature conducive to satisfactory growth of the microorganism, for example, between about 18 to 40 C. and preferably between about and C. Ordinarily, optimum production of the compound is obtained in about 2 to 10 days.
  • the medium normally stays fairly close to neutral, or on the acid side during the fermentation.
  • the final pH is dependent, in part, on the buffers present, if any, and in part on the initial pH of the culture medium which is advantageously adjusted to about pH 68"prior to sterilization.
  • the vegetable form, rather than the spore form, of the microorganisms for inoculation to avoid a pronounced lag in the production of the new compound and the attendant ineflicient utilization of equipment. Accordingly, it is desirable to produce a vegetative inoculum in a nutrient broth culture by inoculating the broth culture with an aliquot from a soil or slant culture. When a young, active, vegetative inoculum has thus been secured, it is transferred aseptically to large vessels or tanks.
  • the medium in which the vegetative inoculum is produced can be the same as, or different from, that utilized for the production of the new compound, as long as it is such that a good growth of the microorganism is obtained.
  • the new compound of the invention is an amphoteric compound having the empirical formula C H Cl NO It has a basic function of about pKa' 8.28. It is soluble in water and lower alkanols, e.g., methanol, ethanol, isopropanol, the butanols, and the like; it is relatively insoluble in chlorinated lower-alkanes, e.g., methylene chloride, chloroform, ethylene dichloride, and the like; loweralkanones, e.g., acetone, methyl ethyl ketone, and the like; higher alcohols, and saturated hydrocarbon solvents.
  • lower alkanols e.g., methanol, ethanol, isopropanol, the butanols, and the like
  • chlorinated lower-alkanes e.g., methylene chloride, chloroform, ethylene dichloride, and the like
  • loweralkanones e.g.,
  • a variety of procedures can be employed in the isolation and purification of armentomycin, for example, solvent extraction, liquid-liquid distribution in a Craig apparatus, the use of adsorbents, and crystallization from solvents.
  • armentomycin is recovered from its culture medium by separation of the mycelia and undissolved solids by conventional means such as by filtration or centrifugation.
  • the antibiotic is then removed from the filtered or centrifuged broth by the use of surface active adsorbents, for example, decolorizing carbon or decolorizing resins, and elution of the adsorbed material with a solvent.
  • surface active adsorbents for example, decolorizing carbon or decolorizing resins
  • a suitable decolorizing resin is Permutit DR (U.S. Patent 2,702,263).
  • the eluates obtained from the surface active adsorbent can be evaporated to dryness to provide an impure preparation of the antibiotic armentomycin. This preparation can be used in environments where higher purity of the antibiotic is not necessary.
  • High purity armentomycin can be obtained by subjecting an impure dry preparation of armentomycin, as obtained above, to liquid-liquid distribution in a Craig apparatus. Prior to the use of the craig apparatus, the dry preparation can be leached with a lower-alkanol; methanol is preferred.
  • the counter-current distribution in a Craig apparatus can be performed using a solvent system consisting of equal amounts of n-butanol and water. Active fractions obtained from the Craig apparatus can be concentrated to an aqueous solution and then freeze-dried. This material can then be obtained as crystalline armentomycin from a solution of a lower-alkanol (ethanol preferred) and water.
  • the new compound of the invention also can be purified by successive transfers from protonated to non-protonated forms and vice-versa, especially with other types of treatments intervening as, for example, solvent extractions and washings, chromatography, and fractional liquidliquid extraction.
  • salts of armentomycin can be employed to isolate or upgrade the antibiotic.
  • the antibiotic can be converted to an insoluble salt, such as the picrate, which can be subjected to purification procedures and then used to regenerate the antibiotic.
  • the antobiotic can be converted to a watersoluble salt, such as the hydrochloride or sulfate, and the aqueous solution of the salt extracted with various waterirnmiscible solvents before regenerating the antibiotic.
  • armentomycin Since armentomycin is an amphoteric substance, it forms salts with acids, alkali metals, alkaline earth metals, and amines. Metal salts can be prepared by dissolving armentomycin in water, adding a dilute metal base until the pH of the solution is about 7 to 8, and freeze-drying the solution to provide a dried residue consisting of the armentomycin metal salt. Armentomycin metal salts include the sodium, potassium, and calcium salts. Amine salts of armentomycin, including those with organic bases such as primary, secondary, and tertiary mono-, di-, and polyamines can also be formed using the above-described or other commonly employed procedures. Other salts are obtained with therapeutically effective bases which impart additional therapeutic elfects thereto.
  • Such bases are, for example, the purine bases such as theophyllin, theo- 'bromin, caffeine, or derivatives of such purine bases; antihistaminic bases which are capable of forming salts with weak acids; pyridine compounds such as nicotinic acid amide, isonicotinic acid hydrazide, and the like, phenylalkylamines such as adrenalin, ephedrin, and the like; choline, and others.
  • the purine bases such as theophyllin, theo- 'bromin, caffeine, or derivatives of such purine bases
  • antihistaminic bases which are capable of forming salts with weak acids
  • pyridine compounds such as nicotinic acid amide, isonicotinic acid hydrazide, and the like, phenylalkylamines such as adrenalin, ephedrin, and the like
  • choline and others.
  • Acid salts of armentomycin can be made by neutralizing armentomycin with the appropriate acid to below about pH 7.0, and advantageously to about pH 2 to pH 6.
  • Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucic, camphoric, glutan'c, glycolic, phthalic, tartaric, lauric, stearic, salicyclic, S-phenylsalicyclic, S-phenylsalicyclic, 3-methylglutanc, ortho-sulfobenzoic, cyclohexanesulfamic, cyclopentanepropionic, 1,2-cyclohexanedicarboxylic, 4-cyclohexenecarboxylic, octadecenylsuccinic, octenylsuccinic, methanesulfonic, benzenes
  • the new compound of the invention can also be recovered from the filtered beer by adsorption on cation exchange resins.
  • carboxylic and sulfonic acid types can be used.
  • Suitable carboxylic acid resins include the polyacrylic acid resins obtained by the copolymerization of acrylic acid and divinylbenzene by the procedure given on page 87 of Kunin, Ion Exchange Resins, 2d ed. (1958), John Wiley and Sons, Inc.
  • Carboxylic acid cation exchange resins of this type are marketed under the trade names Amberlite I'RC-50 and Zeokarb 226.
  • Suitable sulfonic acid resins include nuclear sulfonated polystyrene resins cross-linked with divinylbenzene obtained by the procedure given on page 84 of Kunin, supra.
  • Sulfonated cation exchange resins of this type are marketed under the trade names Dowex50, Amberlite IR-120, Nalcite HOR, Chempro C-20, Permutit Q, and Zeokarb 225.]
  • the antibiotic is eluted from the resin with water at an acid pH, advantageously at a pH lower than the pKa of the cation exchange resin used. Satisfactory results are obtained with a pH of about 1 to 6
  • the excess acid 6 in the eluate is neutralized to about pH 7.5 to 8.5 with a base, e.g., sodium hydroxide, or a strongly basic anion exchange resin, and the antibiotic is extracted with a solvent according to the process described above.
  • a base e.g., sodium hydroxide, or a strongly basic anion exchange resin
  • armentomycin can be separated from the culture medium by use of a strongly basic anion exchange resin.
  • Suitable anion exchange resins for this purpose are obtained by chloromethylating by the procedure given on pages 88 and 97 of Kunin, 'Ion Exchange Resins, 2d ed. (1958), John Wiley and Sons, Inc. polystyrene crosslinked, if desired, with divinylbenzene, prepared by the procedure given on page 84 of Kunin, supra, and quaternizing with trimethylamine or dimethylethanolamine by the procedure given on page 97 of Kunin, supra.
  • Anion exchange resins of this type are marketed under the trade names Dowexl, Dowex-Z, Dowex-3, Amberlite IRA- 400, Duolite A-102, and Permutit 8-1.
  • the new compound of the invention is active against Proteus mirabilis and can be used to minimize or prevent odors caused by this organism in paper mill systems. It can also be used in poultry processing plants to control infections by the organism Salmonella gallinarum.
  • EXAMPLE 1 A soil stock of Streptomyces arment'osus var. armentosus nov. sp., NRRL 3176, was used to inoculate 500 ml. Erlenmeyer flasks containing 100 ml. of sterile pre-seed medium consisting of the following ingredients:
  • the pre-seed medium pre-sterilization pH was 7.2.
  • the pre-seed inoculum was grown for 2 days at 28 C. on a Gump rotary shaker operating at 260 rpm.
  • the pre-seed inoculum (100 ml.) was used to inoculate a 40-liter seed tank containing 20 liters of the following sterile seed medium:
  • the pre-sterilization pH of the fermentation tank medium was 7.2.
  • the fermentation cycle was 4 days during which time the temperature was controlled at 25 C., filtered air was supplied at a rate of 100 standard liters per minute,
  • .assay was 213 biounits per ml. The weight of the whole broth was 263 kg.
  • pool Tubes I 20-40 II 41-60 III 61-80 IV 81-120 V 121-210 VI 211-260
  • Each pool was concentrated to dryness by first concentrating to an aqueous solution in vacuo and then freezedying. Freeze-dried preparations from pools I to V were found to be inactive by the P. mirabilis assay. All the activity was found to be in the freeze-dried preparation (480 mg.) made from pool VI.
  • the Proteus mirabilis assay used throughout this application is a microbiological disc plate assay on synthetic agar adjusted to a pH of 7.0.
  • the synthetic agar used is made by Baltimore Biological Laboratories, Baltimore, Md. It is designated Upjohn Mineral Salts Agar. It has the following ingredients:
  • Infrared spectrum The infrared absorption spectrum of armentomycin suspended in Nujol mull is reproduced in FIG. 1 of the drawing.
  • Armentomycin shows peaks at the following wave lengths expressed in reciprocal centimeters:
  • Armentomycin is soluble in water and lower alcohols, e.g., methanol and ethanol. It is relatively insoluble in less polar solvents, higher alcohols, alkanones, chlorinated hydrocarbons and saturated hydrocarbon solvents.
  • a compound as defined in claim 1 armentomycin, in its essentially pure crystalline form.
  • a process which comprises cultivating an armentomycin-producing strain of Streptomyces armentosus var. armentosus nov. sp. in an aqueous nutrient medium under aerobic conditions until substantial activity is imparted to said medium by the production of armentomycin.
  • a process which comprises cultivating an armentomycin-producing strain of Slreptomyces armentosus Var. armentosus nov. sp. in an aqueous nutrient medium containing a source of assimilable carbohydrate and assimilable nitrogen under aerobic conditions until substantial activity is imparted to said medium by the production of armentomycin and isolating the armentomycin so produced.
  • a process according to claim 7 in which the isolation comprises filtering the medium, adsorbing the armentomycin on a surface active agent, and recovering armentomycin from the adsorbent.

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US448611A 1965-04-16 1965-04-16 Antibiotic armentomycin and a process for producing the same Expired - Lifetime US3342681A (en)

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Application Number Priority Date Filing Date Title
US448611A US3342681A (en) 1965-04-16 1965-04-16 Antibiotic armentomycin and a process for producing the same
GB13338/66A GB1131079A (en) 1965-04-16 1966-03-25 The antibiotic armentomycin
DE19661617902 DE1617902A1 (de) 1965-04-16 1966-04-14 Verfahren zur Herstellung des Antibiotikums Armentomycin
NL6604978A NL6604978A (forum.php) 1965-04-16 1966-04-14
FR57889A FR1487346A (fr) 1965-04-16 1966-04-15 Armentomycine à titre d'antibiotique nouveau

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454696A (en) * 1968-02-19 1969-07-08 Schering Corp Antibiotics 460 and methods for their production
US3458626A (en) * 1968-02-26 1969-07-29 Schering Corp Antibiotics 15 and methods for their production

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA731225B (en) * 1972-03-13 1973-11-28 Upjohn Co Composition of matter and process
CN108048366B (zh) * 2018-01-19 2021-03-30 曲阜师范大学 一株海洋放线菌及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3067099A (en) * 1955-09-16 1962-12-04 Lilly Co Eli Vancomycin and method for its preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3067099A (en) * 1955-09-16 1962-12-04 Lilly Co Eli Vancomycin and method for its preparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454696A (en) * 1968-02-19 1969-07-08 Schering Corp Antibiotics 460 and methods for their production
US3458626A (en) * 1968-02-26 1969-07-29 Schering Corp Antibiotics 15 and methods for their production

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